@article{cb30ad5eb40d49f08ef67f928d564a08,
title = "Allosteric Optical Control of a Class B G-Protein-Coupled Receptor",
abstract = "Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon-like peptide-1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small-molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.",
keywords = "GLP-1 receptor, allosteric regulation, beta cells, photopharmacology, type 2 diabetes",
author = "Johannes Broichhagen and Johnston, {Natalie R.} and {Von Ohlen}, Yorrick and Helena Meyer-Berg and Jones, {Ben J.} and Bloom, {Stephen R.} and Rutter, {Guy A.} and Dirk Trauner and Hodson, {David J.}",
note = "Funding Information: J.B. was supported by an EFSD Albert Renold Young Scientist Fellowship and a Studienstiftung des deutschen Volkes PhD studentship. N.R.J. was supported by a Diabetes UK RW and JM Collins Studentship. H.M.B. was supported by a Bavarian Grant for Studies. B.J.J. was funded by an MRC Clinical Research Training Fellowship. S.R.B. is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA), MRC Programme (MR/J0003042/1), Diabetes UK Project Grant (11/0004210) and Royal Society Wolfson Research Merit Awards. D.J.H. was supported by Diabetes UK R.D. Lawrence (12/0004431), EFSD/Novo Nordisk Rising Star and Birmingham Fellowships, as well as an MRC project grant (MR/N00275X/1). D.J.H. and G.A.R. were supported by Imperial Confidence in Concept (ICiC) Grants. D.T. was supported by an Advanced Grant from the European Research Council (268795). We thank Dr. Peter Mayer (LMU) for X-ray data collection and solving structures and Dr. Jun-ichi Miyazaki for providing MIN6 cells. Publisher Copyright: {\textcopyright} 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
year = "2016",
month = may,
day = "4",
doi = "10.1002/anie.201600957",
language = "English (US)",
volume = "55",
pages = "5865--5868",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "19",
}